Antimicrobial interferon-inducing medicament

ABSTRACT

An antimicrobial and interferon-inducing composition containing the crystalline gamma-modification of para-amino benzenesulfanilamide and a method for inducing interferon by administering a composition containing crystalline gamma-modification of para-amino benzenesulfanilamide.

This application is a 371 of PCT/Ru93/00209 filed Aug. 31, 1993.

FIELD OF ART

The present invention relates to medicine and, more specifically, to anantimicrobial and interferon-inducing medicament.

BACKGROUND OF ART

Widely known in the prior art is administration ofpara-aminobenzenesulfamide (Streptocidum album, Sulfanilamidum), one ofthe chemotherapeutic preparations of sulfanilamide group. Thepreparation exerts an antimicrobial effect with relation tostreptococcus, meningococcus, gonococcus, pneumococcus, colibacillus andsome other bacteria. Said preparation is utilized predominantly in atablet form. Injection forms of said preparation presuppose theirconversion into soluble salts, for example, the formation of solublecompounds through a primary aromatic group. However, this structure isunstable and calls for introducing a stabilizer, i.e. toxic sodiumsulfite (M. D. Mashkovsky "Medicinal Drugs", Moscow, "Meditsina", 1984,vol. 2, p. 275-277; G. A. Melentieva, "Pharmaceutical Chemistry",Moscow, "Meditsina", 1986, p. 285-286). In addition, the antimicrobialeffect of said preparation is exhibited only in presence of an openaminogroup in a para-position to the sulfanilamide group, so that thedegree of its opening and, consequently, its antimicrobial effect welldepend on time and on physiological constants of blood. Thiscurrently-used preparation in a soluble form (Streptocidum Solubile)features a number of negative properties, such as side effectsassociated with administration of a toxic stabilizer, irritant effect,low biological availability.

It is common knowledge that para-aminobenzenesulfanilamide cancrystallize in the form of three polymorphic modifications designated byα-, β-, γ-forms (Journal of Pharmaceutical Sciences, v. 58, 59, No. 7,July 1970, p. 972-975; Journal of Pharmaceutical Sciences of Japan,1942, m.63, No.11, p. 17-19) of which only α-form is used in practicalmedicine. The pharmacokinetic properties of the crystallineγ-modification of para-aminobenzenesulfanilamide have not beendescribed. The use of γ-modification as an active principle of themedicament is unknown. Besides, the use of α-, β- and γ-modifications ofpara-aminobenzenesulfanilamide in the capacity of interferon inducers isnot known either.

It is common knowledge that all inducers of interferon, the mostimportant factor of nonspecific resistance of cells, are divided intotwo groups, viz., natural (viruses and natural two-spiral nucleic acids)and synthetic (polymers and low-molecular preparations) (F. I. Ershov etal, collected works "Interferon Inducers", Moscow, 1982, p. 7-18).

The natural inducers of interferon are highly antigenic, can becontaminated by other dangerous microorganisms and all of them exert atoxic effect in concentrations requisite for displaying sufficientantiviral activity. The same disadvantages are inherent in the majorityof high-molecular synthetic interferon inducers--polycarboxylates andpolynucleotides (type poly () and poly (). They are likewisesufficiently toxic while their synthesis is difficult and economicallyunremunerative.

Clinically promising are also such low-molecular interferon inducers asgossypol analogs, thyloron preparation(2,7-bis-(2-diethylaminoethoxy)-3-fluorenon) and levamisol (-)2,3,5,6-tetrahydro-6-phenyl-imidaso-(2,1-B)-thiazole hydrochloride) (M.D. Mashkovsky, "Medicinal Drugs", Moscow, "Meditsina", 1986, vol. 2 p.169-171).

However, all these preparations are noted for high toxicity and numerousside effects, and, what is more, interferon induction shows up afteradministration of large doses and is effective for a short time only.

DISCLOSURE OF THE INVENTION

The main object of the invention resides in developing a new medicinaldrug possessing an antimicrobial and interferon-inducing effect, a hightherapeutic efficiency, low toxicity, absence of side effects, and inreducing the time of treatment at diminished doses.

This object of attained by providing a medicinal preparation with anantimicrobial and interferon-inducing effect containing an activeprinciple and a pharmaceutic diluent wherein, according to theinvention, the active principle is constituted by a crystallineγ-modification of para-aminobenzenesulfanilamide. The claimed medicamentcan be administered in any pharmaceutically-acceptable form. When usedfor injections it preferably contains 1.0-2.5 wt.-% of active principle.

The claimed medicament used for injections may contain additionally alow-molecular polyvinylpyrrolidone in the following ratio of components,wt.-%:

    ______________________________________    Crystalline γ-modification of para-                          1.5-2.5    aminobenzenesulfanilamide    Low-molecular polyvinylpyrrolidone                          2.0-4.0    Pharmaceutical diluent                          the balance    ______________________________________

The pharmaceutic diluent in the claimed preparation for injections shallpreferably be water for injections.

The claimed medicament may be administered in the form of rectalsuppositories, preferably containing 12.5-17.5 wt.-% of activeprinciple. The pharmaceutic diluent (base) of rectal suppositories maybe any suitable fat, cocoa butter, etc.

The claimed medicament may be prescribed for external use, preferably incombination with 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropirimidine in a50:50 proportion by weight.

The claimed medicament containing, according to the invention, acrystalline γ-modification of para-aminobenzenesulfanilamide for theactive principle, features a high antimicrobial activity which is asgood as that of officially used pharmacopeialpara-aminobenzenesulfanilamide (α-modification), a lower toxicity,improved biological availability and negligible side effects. Due to theimproved biological availability of the claimed medicament, which is2.43 times that of the known pharmacopeical preparation, its therapeuticdose and time of treatment can be reduced and side effects eliminated.Besides, the claimed medicament exhibits a high interferon-inducingactivity (the pharmacopeial para-aminobenzenesulfanilamide lacks suchactivity). A combination of high interferon-inducing activity withantimicrobial activity at a low toxicity and availability renders theclaimed medicament quite promising for a wide range of applications inpractical treatment of infections.

BEST MODE OF CARRYING OUT THE INVENTION

The claimed antimicrobial and interferon-inducing medicament accordingto the invention has an active principle in the form of a crystallineγ-modification of para-aminobenzenesulfanilamide. The toxic propertiesof the claimed medicament have been thoroughly investigatedexperimentally "in vitro" and "in vivo". Acute toxicity of the solutionsof the pharmacopeial and claimed preparations for injections has beeninvestigated on male rats weighing 150-200 g, 2 ml of known preparationwas administered intraperitoneally to each animal in the first groupwhile each animal of the second group received 2 ml of the claimedmedicament containing, wt.-%: γ-modification ofpara-aminobenzenesulfanilamide, 2.0; low-molecular polyvinylpyrrolidone,3.0; water for injections, the balance; the third group of animalsreceived 2 ml of water for injections. The animals were observed for 10days after which the median lethal dose LD₅₀ was calculated. Experimentshave shown that LD₅₀ of the claimed medicament is 1918 mg/kg of animalbody weight while in the pharmacopeial preparation it is 1245 mg/kg ofbody weight.

An analysis of the data gained has revealed a lower toxicity (by 54.4%)of the claimed medicament as compared with the known one.

Toxic effects of the claimed medicament in comparison with those of theknown one have been studied on the basis of a pathomorphologicalexamination of animals' organs followed by a histological assessment.

Microscopic structure of organs has been studied by killing the test andcontrol animals after certain periods of time. Pieces of organs werefixed with a 10-12-% solution of neutral formalin, poured over withparaffin, and sections 8-10 mm thick with colored with hematoxin-eosin.

A histological examination has been conducted on femoral muscles, heart,lungs, liver, kidney, spleen. The histological examination of theinjection form of the known preparation has revealed hemorrhages ofvarious depth (for small to extensive ones) in the zone of intramuscularinjection in the femoral muscles. The muscular tissue in the hemorrhagezone exhibited disturbances in the general structure of muscular fibers(for vanished transverse striction to necrosis.

Intramuscular injection of the claimed medicament for injectionsproduced no pathological changes in the muscles.

Thus, the claimed medicament has no irritating effect inherent in theknown preparation.

Histological examinations of the other organs have shown absence ofsubstantial changes caused by administration of the claimed medicamentas compared with the known one.

Thus, experiments on animals have demonstrated absence of side effectscaused by administration of the claimed medicament.

The specific antimicrobial activity of the claimed medicament wasstudied by a method of serial dilutions. The source solutions were a0.5-% solution of pharmacopeial para-aminobenzenesulfanilamide and γ-modification of para-aminobenzenesulfanilamide--active principle--of theclaimed medicament in a 0.01 n solution of sodium hydroxide. Doubleddilutions of the test solutions were prepared in beef-extract broth witha culture of Staphylococcus aureus added. The inoculum was held for 24 hin a thermostat and the bacteriostatic concentration was assessedvisually.

The tests were carried out with sterile and nonsterile solutions ofpharmacopeial preparation and active principle of the claimedmedicament.

The experiments were conducted three times on three series of testsolutions.

The results of the tests are shown in Table 1.

                  TABLE 1    ______________________________________    Comparative Characteristic of Growth of    Staphylococcus Aureus Culture Acted upon by    Para-Aminobenzenesulfanilamide and by Crystalline    γ-modification - Active Principle - of Claimed Medicament                  Duration (days), Growth (visually)    No.  Test medicament                        0      1    2    3    Control    ______________________________________    1.   Sterile solvent                        none   yes  yes  yes  yes    2.   Pharmacopeial para-                        none   none none yes  yes         aminobenzene-         sulfanilamide    3.   γ-modification of                        none   none none yes  yes         para-aminobenzene-         sulfanilamide    4.   Nonsterile solvent                        none   yes  yes  yes  yes    5.   Pharmacopeial para-                        none   none none yes  yes         aminobenzenesulfa-         nilamide (nonste-         rile medicament)    6.   γ-modification of                        none   none none yes  yes         para-aminobenzene-         sulfanilamide (non-         sterile medicament)    ______________________________________

An analysis of the data in Table 1 gives an evidence that the activeprinciple of the claimed medicament features an antimicrobial activitywhich is as good as that of the pharmacopeial (official) preparation.

The interferon-inducing activity of the claimed medicament as comparedwith the pharmacopeial preparation was tested on mice in vivo.

Experiments were conducted on male mice, line CBA, weighing 10-12 g. Thecell culture was constituted by an inoculated line of cells of mousefibroblasts Z-929. The cells were grown in plastic 96-hole plate (37 C,3.5% CO) in Eagle medium 2 MEM, of 10-% cattle serum. The selected viruswas the virus of encephalocarditis of mice, strain Columbia.

The pharmacopeial preparation and the claimed medicament wereadministered once intraperitoneally to not less than 5 animals in doesof 50, 150 mkg/0.2 ml (0.2 ml per mouse). Blood was drawn from thecarotid artery 5, 24 and 72 h after administration of preparations.Interferon was titrated by determining the suppression of the cytopathiceffect on the cell culture by a micromethod. The results of tests aresummarized in Table 2.

                  TABLE 2    ______________________________________    Dynamics of Interferon Formation in Blood Serum    of Mice after Injection of Test Preparations              Time of blood                        Interferon titers, un/ml                    draw after ad-                                concentrati-                                        concentrati-                    ministration                                on of pre-                                        on of prepa-                    of preparati-                                paration, 50                                        ration, 150    No.  Preparation                    on, h       mkg/mouse                                        mkg/mouse    ______________________________________    1.   Pharma-     5          <20     <20         copeial para-                    24          <20     <20         aminoben-  72          <20     <20         zenesulfanila-         mide    2.   Claimed     5          40-80    80         medicament 24          160     320                    72          <20     <20    3.   Control     5          <20                    24          <20                    72          <20    4.   Mouse serum                    --          640         interferon    ______________________________________

An analysis of test results has demonstrated that the pharmacopeialpreparation has no interferon-inducing activity. At the same time theclaimed medicament has induced interferon in blood serum of mice already5 h after its administering (early interferon) with its activity of40-80 un/ml while after 24 h the interferon titers have reached 160-320un/ml. After 72 h the interferon titers diminished.

A comparison of the test results with the data known from literaturegives ground to a conclusion that γ-modification is a highly-activeinducer of interferon.

A comparative characteristic of activity of the known interferoninducers and that of the claimed medicament is presented in Table 3.

                  TABLE 3    ______________________________________    Comparative Characteristic of Interferon Inducers    Interferon inducer Activity, un/ml    ______________________________________    Active inducer      30-100    High-active inducer                       >100    Poly () Poly ()    >1000    Dextransulfate     60-80    Levamisol          >100    Gossypol            80    Trental             80-160    Euphylline          80    γ-modification of para-                       160-320    aminobenzenesulfanilamide    (active principle of claimed    medicament)    ______________________________________

The data of Table 3 lead to a conclusion that the claimed medicament isa high-active inducer (activity 160-320 un/ml).

For studying the biological availability of the claimed medicament incomparison with the known preparation (Streptocidum solubile) we haveinvestigated the following factors: 1) maximum concentration of the drugin blood; 2) time of reaching a maximum concentration; 3) time changesin the concentration of substance in blood plasma or serum.

Tests were made on rabbits, body weight 3 kg. The doses of preparationwere calculated on the basis of therapeutic doses and were 100 mg/kg.The difference of molecular masses of substances (equimolar relation)was taken in account. Blood was collected 0.5, 1, 2, 4, and 6 hoursafter a single-shot intramuscular injection of the preparation and thesame was analyzed by the Prebsting-Gavrilova method.

The data obtained are summarized in Table 4.

                                      TABLE 4    __________________________________________________________________________    Content of Preparation in Blood after Intramuscular Injection                     Concentration of sulfamilamide in blood,                     mkg/ml, hours after injection    Medicament for injections                     0.5    1      2       4      6    __________________________________________________________________________    Known preparation                      2.5 + 6.8                             9.81 + 3.9                                   6.99 + 1.4                                           5.08 + 0.74                                                  2.94 + 0.78    (Streptocidum solubile)    Claimed medicament, wt.-%:                     12.61 + 3.1                            13.46 + 4.4                                   14.59 + 3.45                                           9.04 + 0.81                                                  7.84 + 0.86    γ-modification of para-    aminobenzenesulfanilamide, 2.0;    polyvinylpyrrolidone, 3.0;    water for injections, the balance    __________________________________________________________________________

The data obtained are an evidence that the biological availability ofthe claimed medicament is 2.43 times that of the known preparation. Thisenables the curative dose of the preparation to be correspondinglyreduced 2.43 times which will contribute to a still stronger smoothingout of its side effects. At the same time, owing to a high biologicalavailability, a therapeutic dose of the claimed medicament can intensifythe bacteriostatic action of the drug, thereby promoting its therapeuticeffect.

The claimed medicament is utilized in the capacity of an antimicrobialand interferon-inducing drug.

The claimed medicament can be administered in anypharmaceutically-suitable medicamentous form. When it is used forinjections, the content of active principle ranges from 1.5 to 2.5wt.-%. Investigations in selecting the optimum concentration of theactive principle have demonstrated that the claimed concentration rangeensures the requisite therapeutic concentration of preparation in blood.The content of active principle in blood below 1.5 wt.-% builds upconcentration which is close to the lower limits of the therapeuticconcentration. Conversely, concentration exceeding 2.5 wt.-% increasesload on the muscular tissue which upsets the general structure ofmuscular fibers. And still higher doses bring about a risk of toxicconcentrations in blood.

The claimed preparation for injections may additionally containlow-molecular polyvinylpyrrolidone in the following proportions ofcomponents, wt.-%:

    ______________________________________    crystalline γ-modification of para-                          1.5-2.5    aminobenzenesulfanilamide    low-molecular polyvinylpyrrolidone                          2.0-4.0    pharmaceutic diluent  the balance    ______________________________________

Introduction of polyvinylpyrrolidone into the preparation is warrantedby its indifference and requisite sedimentation stability andabsorbability of the composition. The time of sedimentation isestablished experimentally.

A higher concentration of polyvinylpyrrolidone increases sedimentationstability. An analysis of concentration of the preparation in blood hasshown that the optimum limits of polyvinylpyrrolidone content in thepreparation is 2-4 wt.-%. The pharmaceutic diluent is, preferably, waterfor injections.

The claimed preparation can be used in the form of rectal suppositoriescontaining, preferably, 12.5-17.5 wt.-% of active principle. An analysisof conducted investigations has shown that administration ofsuppositories containing 12.5-17.5 wt.-% of the active principle ensuresits therapeutic concentration in blood (2.0-20.0 mkg/ml). Thesuppositories may be made on any pharmaceutically-suitable base (fat,cocoa butter, etc.). The claimed preparation can be used for externalapplication in which case its active principle is the crystallineγ-modification of para-aminobenzenesulfanilamide in combination with2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine in a mass proportion of1:1.

The claimed preparation in the form of ointment or powder for externalapplication has been tested clinically in severest cases ofpoorly-healing purulent wounds of various nosological forms (trophiculcers of venous origin: small, up to 5 sq.cm, and large, over 5 sq.cmin size, and postoperative purulent wounds).

The program of tests was accentuated on weakening of the inflammatoryreaction, time of wound cleaning, granulation growth rate, marginalepithelization. For the sake of comparison, the patients were treatedwith the known ointment containing 10 wt.-% of active principle, i.e.4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine.

The use of the claimed preparation for treatment of trophic ulcers ofvenous origin brought about an essential weakening of the inflammatoryreaction in the first two days, stimulated the rate of granulationgrowth and ensured prompt epithelization. Ulcers up to 2 cm in diameterwere healed within 7-10 days (as compared with conventional treatmenttime of 14-18 days). The postoperative purulent wounds 4 to 20 sq.cm insize were quickly cleaned, rubber and inflammatory infiltration on woundedges diminished and vanished, pains subsided on the 2nd or 3rd day,granulations turned bright and fine-grained. The healing time wasreduced twice.

The results of investigations appear in Tables 5 and 6.

                  TABLE 5    ______________________________________    Average Time (days) for Healing Wounds with    Claimed and Known Medicaments                      Healing time (days)                        claimed   known    Nosological form of wounds                        medicament                                  ointment    ______________________________________    Trophic ulcer of venous origin,                        9         16    up to 5 sq.cm in size    Trophic ulcer of venous origin,                        18        35    over 5 sq.cm in size    Purulent postoperative wounds                        8         15    ______________________________________

                  TABLE 6    ______________________________________    Results of Healing Wounds with Claimed Medicament    in Comparison with Known Ointment                 Treatment results                       claimed      known    Nosological              Number   medicament   ointment    form      of       impro-  no prog-                                      impro-                                            no prog-    of wounds patients vement  ress   vement                                            gress    ______________________________________    Trophic ulcers              12       6       --     3     3    of venous origin    Purulent post-              12       6       --     4     2    operative    wounds    ______________________________________

Now the invention will be elucidated by concrete examples of preparingand testing the claimed medicament.

EXAMPLE 1

The medicament was prepared in aseptic conditions.

2 g of low-molecular polyvinylpyrrolidone (molecular mass 12000) wasdissolved in a small amount of water (or injections, the producedsolution was treated with 1.5 g of powder of γ-modification ofpara-aminobenzenesulfanilamide, particle size under 0.1 micron, shakenfor 15-20 s, the volume of produced suspension was brought to 100 ml wasdistilled water for injections, and shaken once more.

The produced medicament for injections is a suspension with an opticaldensity of 2.3. After 5 minutes' settling the optical density was 2.2,pH=6.5.

Five 3-kg rabbits were given intramuscularly, each, 3 ml of preparedsuspension.

After 0.5, 1, 2, 4, 6 hours 1 ml of blood was drawn from the auricularvein of rabbits and analyzed by the known method (Prebsting-Gavrilova).

The obtained experimental data were statistically processed (p=95%).Experimental data are summarized in Table 7.

                  TABLE 7    ______________________________________    Content of Claimed Medicament in Blood after    Intramuscular Injection    Content of medicament in blood (mkg/ml)    0.5 h    1 h       2 h       4 h     6 h    ______________________________________    44.43 + 0.70             5.0 + 0.88                       5.82 + 0.62                                 3.30 + 0.5                                         3.04 + 0.48    ______________________________________

It can be seen from Table 7 that the therapeutic concentration of themedicament in blood is retained in the course of 6 h.

Histological control discovered no changes in internal organs.

EXAMPLE 2

The medicament was prepared in aseptic conditions.

4 g of low-molecular polyvinylpyrrolidone (molecular mass 12000) wasdissolved in a small amount of water for injections and the producedsolution was treated with 2.5 g of powder of γ-modification ofpara-aminobenzenesulfanilamide, particle size 0.1 micron and smaller,shaken for 15-20 s, the volume of the produced suspension was brought to100 ml with distilled water for injections, and shaken once more.

The medicament for injections produced in this way had the form of asuspension with an optical density of 3.2. After 5-minutes' settling theoptical density was 3.0 and pH=6.8.

Five 3-kg rabbits were injected intramuscularly, each, with 3 ml ofprepared suspension.

After 0.5, 1, 2, 4 and 6 hours, 1 ml of blood was drawn from theauricular vein of rabbits and analyzed by the known method(Prebsting-Gavrilova).

The obtained experimental data were statistically processed (p=95%).They are given in Table 8, below.

                  TABLE 8    ______________________________________    Concentration of Claimed Medicament in Blood after    Intramuscular Injection    Concentration of claimed medicament in blood (mkg/ml)    0.5 h   1 h        2 h       4 h     6 h    ______________________________________    9.9 + 0.75            10.62 + 1.90                       11.15 + 2.1                                 7.62 + 1.3                                         6.11 + 1.20    ______________________________________

It can be derived from the Table that the therapeutic concentration ofthe claimed medicament in blood is retained for 6 h.

A histological examination discovered no changes in internal organs.

EXAMPLE 3

Interferon-inducing activity of the claimed medicament was tested asfollows.

Tests were made on 10 male mice, line SVA, weighing 10-12 g each. Thetest culture was the inoculated line of cells of mouse fibroblastsZ-929. The cells were grown in 96-hole plastic plates (37 C, 3.5% CO) inEagle medium MEM of 10-% cattle serum. The virus was of mouseencephalocarditis, strain Columbia.

Five mice were injected with the claimed medicament in a dose of 50mkg/0.2 ml (1st group) and five mice received each, 150 mkg/0.1 mlintraperitoneally (2nd group). Blood was drawn from the carotid 5, 24and 72 h administration of the preparation, interferon was titered bydetermining suppression of cytopathic action on the cell culture by themicromethod.

Already after 5 h the interferon level in blood serum of the 1st groupof mice has reached 40-80 un/ml; after 24 h it increased to 160 un/mland on expiration of 72 h, dropped to 20 un/ml.

In the 2nd group of animals 5 h after administration of the medicamentthe interferon level was 80 un/ml; it rose to 320 un/ml after 24 h whileafter 72 h it dropped to 20 un/ml.

Thus, administration of the claimed medicament in a dose of 50 and 150un/ml produced a considerable increase of interferon titers: up to 40-80un/ml after 5 h and up to 160-320 un/ml after 24 h.

An analysis of test results proves that the claimed medicament featuresa high interferon-inducing activity (160-320 un/ml).

EXAMPLE 4

Preparation and tests of the claimed medicament for rectaladministration.

Suppositories are prepared by pouring-out method. Each suppositorycontains 0.3 g of active principle and 1.7 g ofpharmaceutically-suitable fat base.

The γ-modification of para-aminobenzenesulfanilamide (active principle)is introduced into the melted base in the form of finely-divided powderat a temperature of 40°-45° C. The prepared suppositories are stored fortwo weeks at room temperature. Experiments are carried out on rabbitsweighing 3-3.5 kg. Before introduction of suppositories, the rabbits aregiven a cleansing enema and after introduction the anal orifice is fixedwith a clip.

Blood is drawn from the auricular vein after 0.5, 1, 2, 4 and 6 h.Concentration of medicament in blood is determined by thePrebsting-Gavrilova method. Concurrently, comparative tests are carriedout with the pharmacopeial preparation ofpara-aminobenzenesulfanilamide.

                                      TABLE 9    __________________________________________________________________________    Concentration of Test Rectal Preparations in Blood    (introduction of suppositories)                      Concentration, mkg/ml    No. Preparation   0.5 h   1 h     2 h     4 h     6 h    __________________________________________________________________________    1.  Pharmacopeial preparation                      5.13 + 1.3                              5.83 + 1.4                                      13.32 + 2.15                                              13.72 + 1.29                                                      8.20 + 1.41    2.  Claimed medicament                      17.32 + 1.40                              10.97 + 0.95                                       6.41 + 0.96                                               5.48 + 1.12                                                      3.83 + 1.13    __________________________________________________________________________

An analysis of experimental data submitted in Table 9 illustrates thatrectal suppositories containing the claimed medicament are morebiologically available than those with the pharmacopeial preparation,they ensure maximum concentration already 0.5-1 h after administrationand maintain the therapeutic concentration (within 2-20 mkg/ml) in thecourse of 6 h.

Tests have shown that the animals do not suffer from dyspepticdisorders. After post mortem dissection there were no changes of themucous membrane in the large intestine. Neither was there any distensionof intestines. Filling of mesentery vessels with blood was normal. Ondissection of the rectum the mucous membrane was pallid and macroscopicexamination revealed no hemorrhage foci, necroses and other injuries.

Examination of histological sections fixed in 10% formalin and coloredwith hematoxyline and eosine has shown no substantial deviations fromnormal morphological structure.

An examination of the antimicrobial activity of the claimedsuppositories has confirmed the presence of bacteriostatic effect on Gr+and Gr- microbes.

Thus, the examinations have revealed that the claimed medicament forrectal use exhibits antimicrobial activity, high biological availabilityand no irritating side effects.

EXAMPLE 5

Clinical tests of the claimed medicament for external use.

Patient Z., 52, was admitted to hospital with a diagnosis of chronicvenous insufficiency of the left lower extremity and trophic ulcer ofthe epigastric region 2×3 cm in size. After a Cokket operation thepatient was given traditional medicaments such as dioxidine, vinylineand seabuckthorn oil. The ulcer was healing slowly. Healing wascompleted in 2 months.

Then a sinistral Cokket operation was made. In the course of thepostoperative period the ulcer was treated daily with the claimedmedicament (containing γ-modification of para-aminobenzenesulfanilamidein a mass relation of 1:1) followed by bandaging. Beginning from thesecond day the inflammatory reaction diminished, the wound cleared,granulations and marginal epithelization started growing intensively.Complete healing cam by the 18th day.

Patient K., 56, was admitted to hospital in connection with obliteratingatherosclerosis, Leriche' syndrome. In the postoperative period afteraorto-femoral-bifurcation shunting the operation wound was supported onthe sinistrous side. The sutures were removed and the wound drained. Onthe second day after vanishing of purulent masses the wound was coateddaily with the claimed medicament (containing γ-modification ofpara-aminobenzenesulfanilamide in combination with2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine in a mass relation of1:1) followed by bandaging. Granulation came quickly and epithelizationof the wound was completed in 9 days.

INDUSTRIAL APPLICABILITY

The claimed medicament features antimicrobial and interferon-inducingactivity and is utilized in medical practice.

We claim:
 1. A method of inducing interferon comprising administering toa patient a composition comprising an effective amount of crystallinegamma-modification of para-aminobenzenesulfanilamide in apharmaceutically acceptable diluent or carrier.
 2. A method according toclaim 1 wherein the crystalline gamma-modification of para-aminobenzenesulfanilamide is present in the composition in an amount of from 1.5 to2.5 weight % and said composition is administered to the patient byinjection.
 3. A method according to claim 2 wherein the compositionfurther comprises low molecular weight polyvinylpyrrolidone.
 4. A methodaccording to claim 3 wherein the low molecular weightpolyvinylpyrrolidone is present in an amount of from 2.0 to 4.0 weight%.
 5. A method according to claim 1 wherein the crystallinegamma-modification of para-aminobenzenesulfanilamide is administered ina rectal suppository.
 6. A method according to claim 5 wherein thecrystalline gamma-modification of para-aminobenzenesulfanilamide in thesuppository is present in an amount of from 12.5 to 17.5 weight %.
 7. Amethod for inducing interferon according to claim 1 comprising applyingtopically a composition comprising the crystalline gamma-modification ofpara-aminobenzene sulfanilamide and2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine.